The proposal is intended to address the pathogenesis of Alzheimer paired helical filaments (PHF). The research plan builds upon the recent finding from our laboratory and from other labs that the microtubule-associated protein, tau, is a major antigenic component of the PHF. The importance of tau is not only that all tau antibodies described to date react with Alzheimer neurofibrillary tangles (NFT), but that SDS-extracted PHF as an immunogen consistently results in the development of anti-tau activity. How tau undergoes the molecular transformation which results in PHF is the subject of this proposal, which formalizes an established collaborative effort among a group with expertise in molecular biology, protein chemistry and neuropathology. The uniquely human susceptibility to PHF is addressed in our attempt to sequence the human tau gene and determine the extent of homology with the known mouse sequence. The tau cDNA will be used for in situ hybridization. Whether neurons predisposed to the formation of neurofibrillary tangles contain an enhanced signal will be assessed in Alzheimer and Down syndrome brain. The extension of the tau-immunoreactive neuro-fibrillary tangle into the pyramidal cell apical dendrite suggests an abnormal subcellular locus of tau, which we shall address by determining whether the apical dendritic ribosomes in Alzheimer tissue contain tau mRNA signal. The finding that Alzheimer brain shows regenerative capacity implies that to the extent such phenomena recapitulate development, fetal forms of tau might be re-expressed. We will be able to detect sequences specific to either the 5.5 kb fetal mRNA or 6.0 kb adult mRNA which we have detected in rat brain. Finally the molecular modification of tau which results in PHF may be a phosphorylation event. The aberrant presence of tau in the apical dendrite may make it vulnerable to phosphorylation by type II cAMP-dependent kinase associated with MAP 2. The finding that tau can serve as a substrate for the insulin receptor suggests that the tyrosine kinase, pp60c-src may actually be a more physiologically relevant kinase for tau. The developmental timing and localization of src gene expression show correlates with the expression of microtubule-associated proteins. Enhanced tau phosphorylation may disrupt microtubule polymerization dynamics and result in breakdown of neuronal transport systems and free phosphorylated tau molecules may assemble into PHF.